SUMMARY

• THOR (BLC-3001/NCT03390504) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of BALVERSA vs chemotherapy (docetaxel or vinflunine) or pembrolizumab in patients with metastatic or unresectable urothelial carcinoma (UC) and selected fibroblast growth factor receptor (FGFR) gene alterations that has progressed during or after 1 or 2 prior lines of therapy.^1,2
  • In an analysis of results from cohort 1 (n=266), the safety profiles were reported to be consistent with the known safety profiles of BALVERSA and chemotherapy. Safety results were not described separately for the subgroup of patients with upper tract UC.¹
  • Subgroup evaluation according to primary tumor location demonstrated 16 overall survival (OS) events, 29 progression-free survival (PFS) events, and 26 objective response rate (ORR) events in patients with upper tract disease treated with BALVERSA (n=41). The median OS for these patients was 23.3 months.³
• BLC2001 (NCT02365597) is a phase 2, multicenter, open-label study in adult patients with locally advanced and unresectable or metastatic UC and prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/3 fusion) with disease progression during or following ≥1 line of prior systemic chemotherapy or within 12 months of receiving neoadjuvant or adjuvant chemotherapy, or were chemotherapy-naïve due to cisplatin ineligibility. Efficacy and safety results are described for patients who received a starting dose of BALVERSA 8 mg orally once daily (N=99).^4,5
  • At primary analysis, subgroup evaluation according to primary tumor location demonstrated a confirmed response rate per investigator assessment of 43% (95% confidence interval [CI], 23-64) in patients with upper tract disease, including renal pelvis and ureter (n=23).⁴
  • The final analysis reported PFS and OS according to primary tumor location. The median PFS in patients with upper tract disease (n=25) was 4.2 months (95% CI, 2.8-8.4) and OS was 10.3 months (95% CI, 6.8-15.3).⁵
  • Safety results were not described separately for the subgroup of patients with upper tract UC. Safety results for the study population are described below.
• A rare case of upper tract UC with concurrent pathogenic mutations in FGFR3 (somatic mutation of Ser249Cys) and TP53 with positive PD-L1 expression was reported. The patient had therapeutic responses to PD-1 blockade treatment and retreatment with combination of pembrolizumab and erdafitinib.⁶

CLINICAL DATA

There are no clinical studies of BALVERSA identified in which enrollment was limited to patients with upper tract UC. However, subgroup analyses of the THOR and BLC2001 studies investigated the response to BALVERSA according to primary tumor location and are summarized in this section.

Subgroup Analysis of Phase 3 Study in Patients with Metastatic or Unresectable UC (THOR)

THOR is an ongoing, phase 3, open-label, multicenter study evaluating the efficacy and safety of BALVERSA vs standard of care chemotherapy (docetaxel or vinflunine) or pembrolizumab in patients with metastatic or unresectable UC and selected FGFR gene alterations that has progressed during or after  1 or 2 prior lines of therapy.^1,2

Study Design/Methods^1,2

• Phase 3, randomized, open-label, multicenter study
• A total of 629 patients from 345 study locations were screened for the presence of FGFR gene alterations and assigned to 2 cohorts based on prior treatment with anti-PD-(L)1 agent:
  • Cohort 1 (n=266): prior chemotherapy with anti-PD-(L)1 treatment in combination or maintenance setting (anti-PD-[L]1 alone in cisplatin-ineligible patients only)^1,7
    • Patients were randomized 1:1 to receive:
      • BALVERSA at a starting dose of 8 mg once daily, with uptitration to 9 mg once daily based on day 14 serum phosphate levels (≤9.0 mg/dL and no associated adverse events [AEs]).⁷
      • Chemotherapy (docetaxel 75 mg/m² as a 1-hour intravenous [IV] infusion every 3 weeks [Q3W] or vinflunine 320 mg/m² as a 20-minute IV infusion once Q3W).
  • Cohort 2 (n=351): prior chemotherapy without anti-PD-(L)1 treatment⁸
    • Patients were randomized 1:1 to receive:
      • BALVERSA at a starting dose of 8 mg once daily, with uptitration to 9 mg once daily based on day 14 serum phosphate levels (≤9.0 mg/dL and no associated AEs).⁷
      • Pembrolizumab 200 mg as a 30-minute IV infusion once Q3W.
• Randomization will be stratified by region (North America vs European Union vs rest of the world), Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs 1 vs 2), and disease distribution (presence or absence of visceral metastases: lung, liver, or bone).
• Treatment will continue until disease progression, intolerable toxicity, withdrawal of consent, or decision by the investigator to discontinue treatment.
• Disease assessments by computed tomography (CT) or magnetic resonance imaging (MRI) will be performed every 6 weeks for 6 months followed by every 12 weeks for the next 6 months and then as clinically indicated.
• Tumor responses will be evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Select inclusion criteria: adult patients with stage 4 carcinoma of the urothelium and documented progression; only 1 line of prior systemic treatment for metastatic UC (cohort 1: prior treatment with an anti-PD-(L)1 agent as monotherapy or as combination therapy; ≤2 prior lines of systemic treatment; cohort 2: prior chemotherapy [no prior treatment with an anti-PD-(L)1 agent; only 1 line of prior systemic treatment])²; patients who received neoadjuvant or adjuvant chemotherapy and showed disease progression within 12 months of the last dose are considered to have received systemic chemotherapy in the metastatic setting); tumors with ≥1 select FGFR3 or FGFR2 fusion or mutation determined by central laboratory screening; ECOG PS ≤2; adequate bone marrow, liver, and renal function (creatinine clearance >30 mL/min/1.73 m²); phosphate levels <upper limit of normal (ULN) within 14 days of treatment and prior to first day of cycle 1 day 1 (C1D1).
• Select exclusion criteria: treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days before randomization; active malignancies (ie, requiring treatment change in the last 24 months) other than UC (except skin cancer within the last 24 months that is considered completely cured); symptomatic central nervous system (CNS) metastases; prior FGFR inhibitor treatment; corneal or retinal abnormality including central serous retinopathy (CSR) or retinal pigment epithelial detachment (RPED) of any grade; history of uncontrolled cardiovascular disease or known active human immunodeficiency virus, hepatitis B or C infection.
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, DOR, patient-reported outcomes (Functional Assessment of Cancer Therapy-Bladder Cancer [FACT-B1], Patient-Global Impression of Severity [PGIS], European Quality of Life-5 Dimensions-5 Levels Questionnaire [EQ-5D-5L]), safety, and pharmacokinetics (PK)

Results

• Loriot et al (2023)¹ presented results from cohort 1 (n=266) after a median follow-up of 15.9 months. The median OS was 12.1 months for patients receiving BALVERSA vs 7.8 months for patients receiving chemotherapy. A 36% reduction in risk of death was observed in patients receiving BALVERSA (hazard ratio [HR], 0.64; 95% CI, 0.47-0.88; P=0.005). Median PFS was 5.6 months for patients receiving BALVERSA vs 2.7 months for patients receiving chemotherapy. ORR was 45.6% for patients receiving BALVERSA vs 11.5% for patients receiving chemotherapy. The safety profiles were consistent with the known safety profiles of BALVERSA and chemotherapy.

Efficacy in Cohort 1 by Primary Tumor Location³

• Response to BALVERSA by primary tumor location is shown in the table below.

Safety in Cohort 1 by Primary Tumor Location¹

• Safety results were not delineated according to primary tumor location.
• In the BALVERSA treatment arm (n=135), 62 (45.9%) patients had grade
• 3-4 treatment-related adverse events (TRAEs; most frequent grade 3-4 TRAEs were palmar-plantar erythrodysesthesia syndrome [13 patients, 9.6%], stomatitis [11 patients, 8.1%], onycholysis [8 patients, 5.9%], and hyperphosphatemia [7 patients, 5.2%]), 18 (13.3%) patients had treatment-related serious AEs, and 1 treatment-related death occurred (reported as sudden death).
• In the chemotherapy treatment arm (n=112), 52 (46.4%) patients had grade 3-4 TRAEs (most frequent grade 3-4 TRAEs were neutropenia [15 patients, 13.4%] and anemia [7 patients, 6.2%]), 27 (24.1%) patients had treatment-related serious AEs, and 6 treatment-related deaths occurred (reported as 2 each with febrile bone marrow aplasia and septic shock, 1 each with atypical pneumonia and febrile neutropenia).

Subgroup Analysis of Phase 2 Study in Patients with Locally Advanced or Metastatic UC (BLC2001)

BLC2001 (NCT02365597) is a phase 2, multicenter, open-label study in adult patients with locally advanced and unresectable or metastatic UC and prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/3 fusion) with disease progression during or following ≥1 line of prior systemic chemotherapy or within 12 months of receiving neoadjuvant or adjuvant chemotherapy, or were chemotherapy-naïve due to cisplatin ineligibility. Efficacy and safety results are described for patients who received a starting dose of BALVERSA 8 mg orally once daily (N=99).^4,5

Study Design Methods^4,5

• Phase 2, multicenter, open-label study (NCT02365597)
• Patients were initially randomized 1:1 to 28-day cycles of oral BALVERSA according to either an intermittent regimen or a continuous regimen. Based on interim analysis and pharmacokinetic-pharmacodynamic modeling of serum phosphate levels, the protocol was amended to evaluate a starting dose of continuous BALVERSA 8 mg per day (regimen 3) with a recommended dose escalation to 9 mg once for patients who did not reach target serum phosphate level of 5.5 mg/dL on day 14 and were without treatment-related AEs. Patients whose serum phosphate levels on day 14 were within the target range of 5.5 to <7.0 mg/dL continued to receive BALVERSA 8 mg once daily.
  • Randomization was stratified according to performance status (0-1 vs 2), hemoglobin value, FGFR alteration type, prior treatment status, and presence vs absence of liver, lung, or bone metastases.
  • Treatment was continued until disease progression or unacceptable adverse events.
  • Patients who experienced investigator-assessed disease progression were permitted to continue BALVERSA at discretion of the investigator and sponsor.
• Select inclusion criteria:
  • Patients had locally advanced and unresectable or metastatic UC with measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • Patients had tumor tissues with 1 of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C OR 1 of the following FGFR gene fusions: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7.¹⁰
  • Patients had disease progression during or following ≥1 line of prior systemic chemotherapy or ≤12 months of neoadjuvant or adjuvant chemotherapy.
  • Chemotherapy-naïve patients who were ineligible for cisplatin-based chemotherapy were also enrolled.
  • Prior immunotherapy (eg, immune checkpoint inhibitor) was permitted.
  • An Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 was required.
• Select exclusion criteria:
  • Patients with persistently elevated phosphate levels above the upper limit of normal despite medical management, uncontrolled cardiovascular disease, brain metastases, or known HIV or hepatitis B or C infection were excluded.
• Primary endpoint: confirmed response rate according to RECIST version 1.1 among patients receiving selected regimen of BALVERSA 8 mg daily
  • Responses were assessed by both investigators and independent radiological review committee
  • A preplanned subgroup analysis investigated response by primary tumor location.
• Secondary endpoints: PFS, response duration, OS, safety, response rate in biomarker-specific subgroups, and pharmacokinetics
  • A post hoc subgroup analysis investigated PFS and OS by primary tumor location.

Results

Primary Analysis - Efficacy in Upper Tract UC Subgroup⁴

• Response to BALVERSA was consistent regardless of primary tumor location as shown in the table below.

Final Analysis – Efficacy in Upper Tract UC Subgroup⁵

• The final analysis included 101 patients; 2 patients were enrolled into the 8 mg once daily regimen after the clinical cutoff date for the primary analysis.¹¹
• Response rate according to subgroups was not reported in the final analysis.
• OS by primary tumor location is shown in the table below.

Primary Analysis - Safety⁴

• Safety results were not delineated according to primary tumor location for the primary and final analyses.
• All patients in the overall population treated with BALVERSA 8 mg once daily experienced an AE of any cause during treatment, of which 67% were grade 3 or 4.
• The most common AEs of any cause in the overall population are summarized in the table below.
• Thirteen patients experienced AEs leading to treatment discontinuation, including detachment of retinal pigment epithelium, hand-foot syndrome, dry mouth, and skin or nail events (2 patients each).
• Dose reductions were required in 55 patients, most commonly due to stomatitis (n=16) and hyperphosphatemia (n=9).
• Among the 41 patients who had a dose escalation to 9 mg once daily:
  • 24 (59%) required ≥1 dose reduction
  • 68% experienced grade ≥3 treatment-emergent AEs

• Treatment-related AEs of special interest or clinical importance in the overall population are summarized in the table below.
• The majority (76%) of central serous retinopathy events resolved with a dose interruption or reduction or with the administration of concomitant medication; all unresolved events were grade 1 or 2.

Final Analysis - Safety^5,13

• The safety profile of BALVERSA after a median of 24 months (IQR [interquartile range]: 22.7-26.6) and a median treatment duration of 5.4 months (IQR: 2.8-9) remained consistent with the primary analysis as described above.
• Longer follow-up did not result in any new treatment-related AEs.
• Grade 3-4 treatment-emergent AEs of any causality occurred in 71% (72/101) of patients; 53% (53/101) had events that were considered related to BALVERSA.
• 45% (45/101) of patients had serious AEs; 11% were related to BALVERSA, and no treatment-related grade 4 AEs and no treatment-related deaths occurred.
• 16% (16/101) of patients had AEs leading to treatment discontinuation that were considered related to BALVERSA.
• 27% (27/101) of patients had CSR events; 85% (23/27) were grade 1 or 2.
  • At data cutoff, 63% (17/27) of CSR events had resolved; all 10 unresolved events were grade 1 or 2.
  • Median time to first incidence of CSR was 53 days (IQR: 32-100) for any-grade events and 94 days (IQR:72-154) for grade 3 events; 2/27 (7%) events occurred after 6 months.
  • Dose reduction, interruption, and discontinuation for CSR occurred in 13% (13/101), 8% (8/101), and 3% (3/101), respectively.
    • Three patients had grade 3 CSR events that resolved or lessened in severity to grade 1 following dose reduction or interruption (n=2); or no dose modification (n=1).
    • One patient had grade 3 detachment of retinal pigment epithelium, which initially resolved, but then recurred as a grade 2 event following dose reduction. BALVERSA was discontinued.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 15 October 2024.